The present invention relates to the use of turmeric to augment the healing process of chronic and acute wounds.
The pharmacokinetics involving the safety, toxicity, dose range, and biological properties of turmeric are known, and the agent is readily available in the food store.
The incidence of ulcers in legs is approximately 1% in the adult population, and 3-4% of persons over the age of 65 have a history of these ulcers. These data are derived from the United States and Europe, according to the recent FDA workshop in Washington ("Clinical Trial Issues of Tropical Wound Healing Biologics," Apr. 22-23, 1993). This conference stressed the application of multifactorial growth factors to chronic wounds. Principles underlying the healing of chronic ulcers require control of three local factors: infection, oxygenation, and edema.
The basic process in regard to angiogenesis as it relates to wound healing deals with the capillaries, which consist of endothelial cells and pericytes. These cells do not divide readily but undergo rapid proliferation during spurts of angiogenesis in wound healing. The present inventors have generated experimental evidence showing that turmeric causes endothelial cells to proliferate, indicating that this molecule can be used to augment wound healing.
Turmeric, a yellow powder developed from the plant Curcuma longa, is commonly used as a food colorant in many Indian dishes and imparts a bitter taste. Turmeric is also used as an additive in prepared mustard.
Although it is primarily a dietary agent, turmeric has long been used in India as a traditional medicine for the treatment of various sprains and inflammatory conditions (Rao T S et al., Indian J. Med. Res., 75:574-578, 1982). The active ingredient in turmeric powder is curcumin, which is a completely symmetrical molecule (Govindarajan V S., Crit. Rev. Food. Sci. Nutr., 12:199- 301, 1980). At present, there is no evidence to indicate that habitual consumption of turmeric has any toxic effects in humans and the FAO/WHO has allocated a temporary admissible daily intake of 0-2.5 mg/kg.sup.3 (Vijayalaxmi, Mutat. Res., 79:125-132,1980).
Extensive in vitro and in vivo testing has shown that turmeric inhibits chemically-induced epidermal ornithine decarboxylase activity, epidermal DNA synthesis, and the promotion of skin tumors in mice (Conney A H et al., Adv. Enzyme Regul., 31:385-396, 1991; Huang M T et al., Cancer Res., 48:5941-5945, 1988; Lu Y P et al., Carcinogenesis, 14:293-297, 1993; Azuine M A, Bhide S V, Nutr Cancer, 17:77-83, 1992). Further studies suggest that turmeric also reduces arachidonic acid-induced rat paw and mouse skin edema and markedly inhibits epidermal lipoxygenase and cyclooxygenase activity in vitro (Rao T S et al., Indian J. Med. Res., 75:574-578, 1982; Conney A H et al., Adv. Enzyme Regul., 31:385-396, 1991; Huang M T et al., Cancer Res., 48:5941-5945, 1988). In humans, ingestion of turmeric has demonstrated a bacteriostatic or bacteriocidal effect against organisms involved in cholecystitis and has been used to treat biliary infections (Ramprasad C et al., Ind. J. Phys. and Pharm., 1:136-143, 1957; Lutumski J et al., Planta Med., 26:9-19, 1974 ). Topical application of a turmeric paste for the treatment of scabies has also shown good results (Charles V, Charles S X., Trop. Geogr. Med., 44:178-181, 1992).
It has been recently shown that curcumin decreased p24 antigen production in acutely or chronically infected cells with HIV-1, a paradigm of anti-viral activity (Li C J et al., Proc. Natl. Acad. Sci. USA, 90:1839-1842, 1993). Administration of curcumin in mice significantly reduced the scavenging of peroxides and other activated oxygen species, exhibiting its antioxidant property (Soudamini K K et al., Indian J. Phys. Pharmacol. 36:239-243, 1992). Oral administration of curcumin in human volunteers has been shown to significantly decrease the level of serum lipid peroxides (33%), increase HDL cholesterol (29%), and decrease total serum cholesterol (11.63%) (Soni K B, Kuttan R., Indian J. Phys. Pharmacol., 36:273-275, 1992).
The addition of turmeric to diet has been shown to inhibit azoxymethanol-induced colonic epithelial cell proliferation and focal areas of dysplasia (Huang M T et al., Cancer Letters, 64:117-121, 1992). It has also been shown to interfere with the formation of covalent carcinogen-DNA adducts (Mukudan M A et al., Cardnogenesis, 14:493-496, 1993).
Fat metabolism is likewise influenced by curcumin. It can render bile non-lithogenic in mice (Hussain M S et al., Indian J. Med. Rcs., 96:288-291, 1992). Curcumin can reduce the production of PMA-induced lipid peroxidation and 8-OH-deoxyguanosine formation in mouse fibroblast cells (Shih C-A, and Lin J-K, Carcinogenesis, 14:709-712, 1993).
Phosphorylation events can also be influenced by curcumin, as it has been reported that curcumin inhibits protein kinase C activity induced by 12-O-tetradecanoyl-phorbol-13-acetate in NIH 3T3 cells (Liu, J-Y, Lin, S-J, and Lin, J-K., Carcinogenesis, 14:857-861).
Curcumin inhibits the immune as well as the smooth muscle cell proliferation. Human peripheral blood mononuclear cells were inhibited in response to phytohemagglutinin and mixed lymphocyte reaction. Furthermore, curcumin inhibited the proliferation of rabbit vascular smooth muscle cells stimulated by fetal calf serum. Curcumin had a greater inhibitory effect on platelet derived growth factor-stimulated proliferation than on serum-stimulated proliferation (Huang H-C et al., Eur. J. Pharmacol., 221:381-384, 1992).
The anti-inflammatory properties of curcumin were shown to inhibit the 5-lipoxygenase activity in rat peritoneal neutrophils as well as the 12-lipoxygenase and the cyclooxygenase activities in human platelets (Ammon H P T et al, J. Ethopharmacol., 38:113-119, 1993). Curcumin had no significant effect on quercetin-induced nuclear DNA damage, lipid peroxidation and protein degradation and thus has the unique potential of acting as both pro- and antioxidants, depending on the redox state of their biological environment (Saura C et al., Cancer Letters, 63:237-241, 1992).